TMEM16A has been identified as a calcium activated chloride channel (see, e.g., Yang et al., Nature, 455:1210-1215 (2008)). It is also known by some other names, such as ANO1, TAOS2, ORAOV2, and DOG-1. TMEM16A belongs to the anoctamin/TMEM16 family of membrane proteins. This family includes other members, such as TMEM16B-K. All TMEM16 proteins have similar putative topology, consisting of eight transmembrane segments and cytosolic N- and C-termini (see, e.g., Galietta, Biophysical J. 97:3047-3053, (2009)).
Calcium activated chloride channels functions in many physiological processes, including transepithelial secretion, cardiac and neuronal excitation, sensory transduction, smooth muscle contraction, and fertilization. TMEM16A is potentially involved in epithelial fluid secretion, olfactory and phototransduction, neuronal and cardiac excitability, and regulation of vascular tone including gut motility (see, e.g., Galietta, 2009).
TMEM16A is also highly over expressed in some cancers, for example, gastrointestinal stromal tumor (“GIST”), and head and neck cancer. TMEM16A is located on chromosome 11q13 and it appears that amplification of this chromosomal region occurs in many tumors including almost half of oral squamous cell carcinomas (Huang et al., Genes Chromosomes Cancer 45:1058-1069, (2006)), and neck squamous cell carcinomas (Cares et al., Oncogene 25:1821-1831, (2006)).
GIST is the most common mesenchymal tumor found in the gastrointestinal tract. There is a high unmet medical need due to refractory, metastatic or resistant GIST. There is also a high unmet medical need to other cancers in which TMEM16A has been implicated.